Polyphosphoinositides are involved in many signal transduction pathways in eukaryotic cells. The first committed step is catalysed by phosphatidylinositol 4-kinase leading to the formation of phosphatidylinositol 4-phosphate. In the last four years, ten cDNA molecules have been cloned which code isoforms of phosphatidylinositol 4-kinase; some of which are highly related. Characteristically, they contain a C-terminal catalytic domain which is similar to that of (poly)phosphoinositide 3-kinases and to that of more distantly related lipid/protein kinases. Alignment has characterised cDNAs from Chaenorabditis, Dictyostelium and Schizostaphyloccus pombe as those of phosphatidylinositol 4-kinases also. All these lipid kinases are related to the superfamily of protein kinases. Several amino acids are highly conserved in catalytic domains of lipid and protein kinases. Employing the catalytic subunit of the cAMPdependent protein kinase as template, these residues can be assigned functionally. On the basis of the alignment, a phylogenetic tree of the superfamily of phosphatidylinositol kinases has been constructed. Three families, the phosphatidylinositol 4-kinases, phosphoinositide 3-kinases, and the phosphatidylinositol related lipid/protein kinases, can be recognised. Each family comprises two subfamilies. The involvement of the phosphatidylinositol 4-kinases in signal transduction processes is summarised and a new hypothesis for the function of their isoforms in polyphosphoinositide signalling is presented. The involvement of phosphatidylinositol 4-kinases in formation of lipidϪprotein interactions with cytoskeleton proteins and the metabolism of polyphosphoinositide in the nucleus is discussed.Keywords : phosphatidylinositol 4-kinase; types and genes of phosphatidylinositol 4-kinases; domain structure ; phylogeny; inositide phospholipid signaling; phosphatidylinositol 4,5-bisphosphate; phosphatidylinositol 4-phosphate ; vesicular traffic; phosphatidylinositol transfer protein.The phosphatidylinositol cycle (Hokin and Hokin, 1953), an the hydrophobic backbone, diacylglycerol, activates protein kinase C (Mitchell et al., 1991; Clapham, 1995). In eukaryotes increase in receptor-stimulated polyphosphoinositide turnover, has been in the focus of attention for more than four decades. A this is one of the most commonly used signalling pathways in a wide range of cells and may be surpassed only by cAMP which highlight was the discovery of two second messengers, inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3] and diacylglycerol, which are is used also in prokaryotes (de Gunzburg, 1985).In the last decade, it has become increasingly clear that polyproduced from phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ) by phospholipase C (PLC). The hydrophilic headgroup, phosphoinositides cover a wider variety of functions other than just being second-messenger precursors. In addition to being Ins(1,4,5)P 3, mobilises Ca 2ϩ from intracellular stores whereas phosphorylated at the D4 and D5 positions of the inositol ring, arrangement (Whit...
Interleukin-6 (IL-6) is a major regulator of the acute phase reaction in the liver and is thought to mediate protective effects in response to hepatotoxins. In this study, the influence of bile acids on IL-6 signal transduction was analyzed. It was shown that hydrophobic bile acids such as glycochenodeoxycholate (GCDC) inhibited IL-6 -induced tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 3 in hepatocytes and in perfused rat liver. This inhibition was accompanied by GCDC-mediated downregulation of glycoprotein (gp) 130 expression, whereas gp130 and suppressor of cytokine signaling 3 messenger RNA and gp80 protein levels remained unaffected. The GCDC-induced downregulation of gp130 protein expression was insensitive to inhibition of proteasomal or lysosomal protein degradation but turned out to be sensitive to inhibition of caspase-3 or caspase-8 activity. Accordingly, treatment of cell extracts with active recombinant caspase-3 led to a decay of immunoreactive gp130. Moreover, activation of caspases by CD95 ligand or hyperosmotic stress also resulted in a downregulation of gp130 levels. This indicates that caspase activation antagonizes IL-6 signaling by decay of gp130 levels. However, caspase inhibition did not prevent GCDC-dependent inhibition of IL-6 -induced STAT3 activation, which turned out to be at least partially sensitive to suppression of p38 MAPK activation. In conclusion, hydrophobic bile acids compromise IL-6 signaling through both a caspasemediated downregulation of gp130 and a p38 MAPK -dependent inhibition of STAT3 phosphorylation. This may contribute to bile acid-induced hepatotoxicity in cholestasis through counteracting the known hepatoprotective effects of
The data show a differential regulation of hepatic transport systems during liver regeneration.
The distribution and cellular localisation of the phosphatidylinositol 4-kinase isoforms, PI4K230 and PI4K92, that are believed to play important roles in the intracellular signalling mechanisms were studied in the rat brain (cortex, cerebellum, hippocampus and spinal cord) using immunocytochemistry with light and electron microscopy. PI4K230 was detected with a specific antibody purified by affinity chromatography from the egg yolk of chicken immunised with a 33-kDa fragment of bovine PI4K230, comprising amino acids 873-1175 of the native protein. PI4K92 was immunostained with a commercially available antibody raised in rabbit against amino acid residues 410-537 of human PI4K92. At the light microscopic level, the immunostaining of PI4K230 and PI4K92 showed a very similar distribution throughout the neurons and appeared as dense punctate labelling in the cytoplasm of perikarya and stem dendrites of various neurons. In addition to neurons, a strongly stained cell population was observed in the molecular layer of the cerebellar cortex that resembled Bergmann glia cells. Electron microscopy of neurons in the ventral horn of the spinal cord showed dense granular immunoprecipitates for both PI4K230 and PI4K92, mostly associated with the outer membrane of mitochondria and membranes of the rough endoplasmic reticulum. In addition, immunostaining of PI4K92 was also frequently found on the outer surface of cisterns and vesicles of Golgi complexes, whereas PI4K230 immunoreactivity was colocalised with some multivesicular bodies. Neither nuclear localisation nor a regular attachment to the cell membrane of these enzymes were observed. Our findings indicate that PI4K230 and PI4K92 are not involved directly in the ligand-stimulated turnover of phosphoinositides at the plasma membrane of neurons. However, they may provide regulatory phosphoinositides for intracellular vesicular traffic being associated with various organelles.
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